Method for Altering the Shape of Polymer Particles

ABSTRACT

A process for altering the shape of a polymer particle is disclosed. The process comprises suspending polymer particles in a suspending medium at a temperature that effects melting of the polymer and agitating the suspension for a time sufficient to change the shape of the particles. The shape altered particles are combined with a pharmaceutically acceptable agent to give a drug delivery particle system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 60/863,327, filed on Oct. 27, 2006,which is incorporated by reference in its entirety herein.

TECHNICAL FIELD

The present disclosure is directed to a method for altering the shape ofpolymer particles by agitating the particles in a suspending solution atan elevated temperature (i.e. at or above the melting point of thepolymer) for a period of time necessary to effect a change in shape ofthe polymer particles.

BACKGROUND

The shape of a polymer particle may alter the biological, physical, ormechanical properties of the particle. Irregularly shaped particles mayhave non-predictable surface area-to-particle ratios, hampering thepredictability of surface modifications, altering degradation rates, anddefeating attempts at sorting for size or other properties. Irregularshapes can have other undesirable physical properties, e.g., they cancause catheter blockage when embolizing a tumor. Removing angles orirregularities from a polymer particle obviates many of these problems.

“Spheronization” is a term commonly understood to mean or to describe aprocess by which a particle (initially non-spherical in shape) is madespherical. The most common example of this process is the conversion ofwet-mass extrudate of microcrystalline cellulose into spheres. Wet-massextrusion typically involves mixing, at a minimum, microcrystallinecellulose and water to form a paste, then pushing the mixture through anopening to create an extrudate of a desired form. This extrudate cantake the form of a strand, and the strand can be cut into particles.These particles are malleable at room temperature and can easily be madespherical by subjecting them, in batch fashion, to the action of aspheronizer. A spheronizer is a metal drum with a rapidly spinning diskon the bottom that converts wet-mass extruded particles into spheres bycausing them to hit each other, the wall of the spheronizer, and thespinning disk, deforming the particles randomly until a spherical shapeis obtained. This process typically takes less than 15 minutes at roomtemperature. The rapid spheronization of wet-mass extruded particles isfacilitated by the particles' malleability.

SUMMARY

Altering the shape of a polymer particle is accomplished by immersingone or more initial polymer particles in a suspending medium at atemperature at or above the melting point of the polymer. The particlesare agitated at this temperature for a period of time to allow a shapechange to occur. In one example, the process can produce a sphericalparticle (i.e. “spheronization”).

The shape altered polymer particles made by the method of the disclosurehave a wide a variety of uses. They can be used, for example, in medicaldevices, as drug delivery vehicles (particles), as particles for use inchromatography (size exclusion, ion exchange, etc.), and in themanufacturing of various types of plastics.

Provided herein is a method of altering the shape of polymer particles,the method includes suspending the polymer particles in a suspendingmedium at a temperature that effects melting of the polymer; andagitating the suspension for a time sufficient to effect a change inshape of the particles to result in shape altered polymer particles. Incertain embodiments, the method can also include cooling the suspensionbelow the melting temperature of the polymer to maintain the alteredshape of the particles. The shape altered particles can further becollected.

The polymer particles can be selected from one or more of polyvinylalcohol (PVA); polystyrene; polycarbonate; polylactide; polyglycolide;lactide-glycolide copolymers; polycaprolactone; lactide-caprolactonecopolymers; polyhydroxybutyrate; polyalkylcyanoacrylates;polyanhydrides; polyorthoesters; albumin; collagen; gelatin;polysaccharides; dextrans; starches; methyl methacrylate; methacrylicacid; hydroxylalkyl acrylates; hydroxylalkyl methacrylates; methyleneglycol dimethacrylate; acrylamide; bisacrylamide; cellulose-basedpolymers; ethylene glycol polymers and copolymers; oxyethylene andoxypropylene polymers; polyvinyl acetate; polyvinylpyrrolidone;polyvinylpyridine; polyanhidrides; and latex.

In certain embodiments, the polymer particle can include anon-biological polymer. In some embodiments, the polymer particles areselected from polylactide, polyglycolide, and poly(lactic-co-glycolicacid) (PLGA). In one embodiment, the polymer particles are PLGA. PLGAcan be composed of a ratio of polylactide to polyglycolide from about90:10, about 75:25. about 65:35, and about 50:50.

The initial polymer particles can be produced by one or more of heatextrusion/pelleting, grinding, and cryo-grinding.

In other embodiments, the polymer particle further comprises apharmaceutically acceptable agent. This pharmaceutically acceptableagent can be selected from a small molecule (e.g., small molecule drugor prodrug), a carbohydrate, a lipid, a protein, or a nucleic acid.

In the method, the initial particles are suspended in a suspendingmedium. The suspending medium can be an aqueous medium (e.g., water orsaline). In some embodiments, the aqueous medium can further includeTris, Tyrodes, phosphate, citrate, or carbonate buffers. In addition,the aqueous medium can include an additional component that prevents thepolymer particles from coalescing or aggregating (e.g., polyvinylalcohol, a polypeptide, a detergent, or a hydrocarbon).

The shape altered polymer particle can be rigid or elastic and mayfurther be biodegradable. The shape altered polymer particles can bespherical, elliptical, elongated, bowling pin, egg, or oval shaped. In apreferred embodiment the shape altered polymer particles are spherical.The longest dimension of the shape altered polymer particles is about 5μm to about 5,000 μm. In the case of a spherical particle, the diameteris about 5 μm to about 5,000 μm.

Further provided is a method of preparing a spherical polymer particle,the method includes suspending non-spherical polymer particles in asuspending medium at a temperature that effects melting of the polymer;and agitating the suspension for a time sufficient to effect a change inshape of the particles to result in spherical polymer particles. Incertain embodiments, the method can also include cooling the suspensionbelow the melting temperature of the polymer to maintain the sphericalshape of the particles. The spherical particles can further becollected.

A drug delivery particle can be prepared through the method ofsuspending an initial polymer particle in a suspending medium at atemperature that effects melting of the polymer; agitating thesuspension for a time sufficient to effect a change in shape of theinitial particles to result in shape altered particles; andincorporating a pharmaceutically acceptable agent into the initial orthe shape altered particles. The incorporation of a pharmaceuticallyacceptable agent into the polymer particles can occur during productionof the initial polymer particles, during agitation of the suspension,and/or after obtaining shape altered particles. In certain embodiments,the drug delivery particle is spherical.

A spherical particle can be prepared through the method of suspending apolymer particle in a suspending medium at a temperature that effectsmelting of the polymer; and agitating the suspension for a timesufficient to effect a change in shape of the particles to result inspherical particles.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1. is an SEM image of an example initial polymer particle. In thisexample, the initial polymer particle is a cylinder of 75:25 PLGA.

FIG. 2 is an photographic image of a shape altered polymer particle. Inthis example, the shape altered polymer particle is a spherical particleof 75:25 PLGA. The photographs were taken on a Hund H500 lightmicroscope with a Nikon D70 digital SLR camera, with a microscopeadapter. The photographs are taken at 40× magnification.

DETAILED DESCRIPTION

As used herein, “agitation” or “agitating” includes stirring, shaking,end-over-end mixing, aspiration, and/or bubbling with gas (e.g., air,nitrogen, or an inert gas such as helium or argon).

As used herein, “suspending medium” refers to an aqueous of non-aqueoussolution in which the polymer particles are not soluble.

Provided herein are methods of altering the shape of polymer particles,for example, from non-spherical to spherical. The process of alteringthe shape of a polymer particle occurs because the polymer particle isheated at or above its melting point in a solution in which the polymeris not soluble. This allows the polymer to act as a fluid droplet. Afluid moving independently in another fluid is subject to surfacetension, a force that acts with even distribution across the surface,and the pressure of the second fluid. A molten droplet of polymer, underthe appropriate conditions, will assume a lowest-energy shape that isthe result of the interaction of the surface tension of the polymer andthe pressure of the aqueous solution that surrounds it. The pressure ofthe aqueous solution acts with equal force at all points on the surfaceof the droplet, and the surface tension of the droplet will act tocreate the lowest-energy conformation. One example of this phenomenon isthe shape of raindrops. Raindrops are different shapes depending ontheir size; small raindrops (radius <1 millimeter (mm)) are spherical,while larger ones assume a shape more like that of a hamburger bun. Theshape results from a tug-of-war between two forces: the surface tensionof the water and the pressure of the air pushing up against the bottomof the drop as it falls. When the drop is small, surface tension winsand pulls the drop into a spherical shape. With increasing size, thefall velocity increases and the pressure on the bottom increases causingthe raindrop to flatten and even develop a depression.

The method of altering the shape of a polymer particle is not limited bythe material that may be used in forming the initial particles. Anymaterial may be used provided that it is thermally plastic and able toundergo shape change when heated and to maintain a final shape whencooled. The materials most amenable to use are biological andnon-biological polymers. Of particular interest are non-biologicalpolymers. These polymers may include chemically functionalized polymers,chemically inert polymers, biologically active polymers, biodegradablepolymers, and labeled polymers (including those polymers labeled with adrug, dye, isotope, chelate, antibody, etc.). Polymers can also becopolymers, block copolymers, etc.

Exemplary non-biological polymers include polyvinyl alcohol (PVA);polystyrene; polycarbonate; polylactide; polyglycolide;lactide-glycolide copolymers; polycaprolactone; lactide-caprolactonecopolymers; lactide-glycolide caprolactone copolymers;polyhydroxybutyrate; polyalkylcyanoacrylates; polyanhydrides;polyorthoesters; methyl methacrylate; methacrylic acid; hydroxylalkylacrylates; hydroxylalkyl methacrylates; methylene glycol dimethacrylate;acrylamide; bisacrylamide; ethylene glycol polymers and copolymers;oxyethylene and oxypropylene polymers; polyvinyl acetate;polyvinylpyrrolidone; polyvinylpyridine; polyanhidrides (e.g., maleicanhydride); and latex.

Non-limiting examples of biological polymers include albumin; collagen;gelatin; polysaccharides; dextrans; starches; and cellulose-basedpolymers.

In certain embodiments the polymer is polylactide. In another embodimentthe polymer is polyglycolide. In some embodiments the polymer ispoly(lactic-co-glycolic acid) (PLGA). The ratio of polylactide topolyglycolide in PLGA can be about 90:10, about 75:25, about 65:35, orabout 50:50.

The initial polymer particles can be initially produced by variousmethods including heat extrusion through a dye followed by cutting toform particles. The particles can also be produced using a grindingmethod that breaks the polymer into chunks. In one embodiment thepolymer particles are produced by heat extrusion/pelleting. In anotherembodiment the polymer particles are produced by grinding. In furtherembodiments the polymer particles are produced by cryo-grinding.

Initially, the polymer particles can be of any shape, e.g., withoutlimitation, irregular and without any shape, barrel-shaped, cylindrical,cubic, rhomboid or amorphous. The particles can be of any convenientsize and are generally in the range of about 5 Tm to about 5,000 Tm intheir longest axis (dimension) (e.g., about 5 Tm to about 2,500 Tm,about 5 Tm to about 1000 Tm, about 5 Tm to about 500 Tm, about 5 Tm toabout 100 Tm, about 25 Tm to about 5,000 Tm, about 100 Tm to about 5,000Tm, about 500 Tm to about 5,000 Tm, about 1,000 Tm to about 5,000 Tm,about 2,500 Tm to about 5,000 Tm, about 50 Tm to about 2,500 Tm, about100 Tm to about 1,500 Tm, and about 250 Tm to about 750 Tm). Particlesof varying size and shape can be altered at the same time. However, itis preferred to alter the shape of particles of similar shape and sizein any given procedure. Thus, in certain embodiments the polymerparticles are of a similar size.

Initial polymer particles are suspended in a suspending medium. Thesuspending medium can be an aqueous or non-aqueous fluid medium. Incertain embodiments, the suspending medium is an aqueous solution.Aqueous solutions include any aqueous solution in which the describedalteration can occur. Such solutions include, for example, water orsaline, and can contain buffers such as Tris, Tyrodes, phosphate,citrate, or carbonate. The solutions can contain additional additivesthat prevent the particles from coalescing or aggregating; for example,polyvinyl alcohol (PVA), one or more polypeptides (e.g., bovine serumalbumin), detergents, and hydrocarbons. In certain embodiments theadditive is polyvinyl alcohol.

Altering the shape of an initial polymer particle can be accomplished byimmersing the initial polymer particles in the suspending medium at atemperature at or above the melting point of the polymer. One ofordinary skill in the art will understand that the necessary temperaturerequired to achieve an alteration in the shape of a polymer particlewill vary based on the polymer used and the final shape desired. Forexample, spherinization of non-spherical polymer particles of 75:25 PLGAcan occur at temperatures from about 70° C. to about 90° C. In anotherexample, non-spherical particles of 50:50 PLGA can be made spherical attemperatures from about 60° C. to about 70° C.

The particles are agitated at this temperature for a period of time toallow a shape change to occur. In one example, spherical particles areproduced by stirring a suspension of polymer particles with a magneticstirbar. In another example, ovoid particles are produced by stirring asuspension of polymer particles with a magnetic stirbar, at a higherstir rate than that used to produce spherical particles. In anotherexample, spherical particles are produced by end-over-end mixing in aclosed vial. In some cases, the polymer particles can be agitated fromone to 24 hours (e.g., 4 to 24 hours, 4 to 18 hours, 4 to 12 hours, 4 to8 hours, 6 to 20 hours, 8 to 24 hours, 10 to 16 hours, 2 to 3 hours, 2to 6 hours, 5 to 15 hours, and 8 to 12 hours). For example,spheronization of 75:25 PLGA cylinders of approximately 1 mm can bespherionized in about 4 to 18.5 hours at 80° C.

Altered particles can have many shapes, including spherical, elliptical,elongated, bowling pin, egg, and oval. Typically, the final shape iscontinuously smooth with no sharp edges. Thus, the method can also beused to smooth a particle to remove one or more edges.

In certain embodiments, the altered particles, are spherical. Sphericalproducts of the method can be of any useful diameter but are generallyin the range of about 5 Tm to about 5,000 Tm (e.g., about 5 Tm to about2,500 Tm, about 5 Tm to about 1000 Tm, about 5 Tm to about 500 Tm, about5 Tm to about 100 Tm, about 25 Tm to about 5,000 Tm, about 100 Tm toabout 5,000 Tm, about 500 Tm to about 5,000 Tm, about 1,000 Tm to about5,000 Tm, about 2,500 Tm to about 5,000 Tm, about 50 Tm to about 2,500Tm, about 100 Tm to about 1,500 Tm, and about 250 Tm to about 750 Tm).Non-spherical products of the method are generally about 5 Tm to about5,000 Tm in their longest dimension (e.g., about 5 Tm to about 2,500 Tm,about 5 Tm to about 1000 Tm, about 5 Tm to about 500 Tm, about 5 Tm toabout 100 Tm, about 25 Tm to about 5,000 Tm, about 100 Tm to about 5,000Tm, about 500 Tm to about 5,000 Tm, about 1,000 Tm to about 5,000 Tm,about 2,500 Tm to about 5,000 Tm, about 50 Tm to about 2,500 Tm, about100 Tm to about 1,500 Tm, and about 250 Tm to about 750 Tm). The finalshape of a polymer particle can be determined, for example, visuallywith the aid of a light microscope, using laser diffraction, by digitalphotographic shape analysis software, or by other methods known in theart.

In one preferred embodiment, the process can produce a sphericalparticle (i.e. “spheronization”). The spheronization process convertsinitial polymer particles created by various processes includingmelt-extrusion/pelleting to discrete, spherical particles.Melt-extrusion (or heat-extrusion)/pelleting is the process in which apolymer is melted and the melted polymer is pushed through a die to forman extrudate. A polymer, e.g., poly(lactic-co-glycolic acid) (PGLA), isintroduced into a screw and heated as it is compacted and pushed by thescrew. The molten polymer is pushed through a hole located at the end ofthe screw, creating a strand. This strand is then cooled and introducedinto a pelleter, which consists of a spinning cutting head or anoscillating “guillotine” cutting blade that cuts the strand intopellets. The initial polymer pellets (i.e. particles) are converted to aspherical shape by introducing them into an aqueous or non-aqueous fluidmedium, depending on the composition of the polymer, at a definedtemperature and agitated for a given period of time. The temperaturechosen should be at or above the melting temperature of the polymer.Once a spherical shape has been achieved, the suspension is cooled belowthe melting temperature of the polymer to maintain the spherical shapeof the particles. For example, the shape altered polymer particles canbe cooled slowly at room temperature with stirring, quickly cooledusing, for example, an ice bath of liquid nitrogen, or by other meansknown in the art.

The shape altered polymer particles are then collected and stored belowthe melting temperature of the polymer. Polymer particles may becollected by any means known in the art, e.g., filtration.

The altered polymer particles made by the method of the disclosure havea wide a variety of uses. They can be used, for example, in medicaldevices, as drug delivery vehicles (particles), as particles for use inchromatography (size exclusion, ion exchange, etc.), and in themanufacturing of various types of plastics. Spherical polymer particlesare well-known in the art as medical devices (Embosphere Microspheres(Biosphere Medical)), Contour SE (Boston Scientific), and as drugdelivery vehicles (Lupron Depot (TAP Pharma)). PLGA has also been usedas a drug delivery vehicle, most commonly in depot applications,including, for example: Risperdal Consta (atypical psychosis; Janssen)in which 25 mg, 37.5 mg or 50 mg of risperidone are encapsulated in PLGAmicrospheres at a concentration of 381 mg of risperidone per gram ofPLGA; Lupron Depot, 3-month, 11.25 mg (NDA 20-708) a drug productcomprised of inter alfa 11.25 mg leuprolide acetate and a carrier of 99mg poly(lactic acid) that is administered as an intramuscular injectionevery three months for the management of endometriosis and anemia causedby uterine fibroids; Sandostatin LAR (somatostatin mimic; Novartis) inwhich 11 mg, 22 mg or 34 mg of octreotide acetate are encapsulated in189 mg, 378 mg or 566 mg of PLGA respectively; and Trelstar Depot (LHRHagonist, Watson Labs) in which 3.75 mg of triptorelin pamoate areencapsulated in 170 mg of PLGA. In addition, the polymer particles canbe used to deliver a chemotherapeutic agent to a tumor via a catheter(see, e.g., U.S. Pat. Nos. 6,900,352 and 6,887,474 and U.S. PublicationNos. 2007/0098724, 2005/0287189, 2005/0287145, 2005/0079179,2003/0082224, and 2002/0168366).

When the polymer particles are used as a medical device or as a drugdelivery agent, the polymer particles can further include one or moreadditional components, e.g., a pharmaceutically acceptable agent (e.g.,small molecule drug or prodrug, chemotherapeutic, HSA, collagen,diagnostic or imaging agent, carbohydrate, lipid, polypeptide, ornucleic acid (e.g., SiRNA). One suitable example of a polypeptide is anantibody or antibody fragment. The additional component may beincorporated either physically (e.g., encapsulated, absorbed, or coatedon the surface) or chemically (e.g., covalently or non-covalently bound)into the polymer particle at any point in the production of the polymerparticle. For example, the additional agent may be incorporated duringsynthesis of the polymer, during production of the initial polymerparticle, during the process of altering the shape of the particle, orafter the final shape of the polymer particle has been achieved. In someinstances, the additional agent is covalently or non-covalently bound tothe polymer particle. In other instances the additional agent isencapsulated in the polymer particle. Suitable linkers for chemicallylinking the additional component are well known and can bebiodegradable.

EXAMPLES Example 1

In this representative example, the ratio of suspending fluid to mass ofparticles was 100 mL:1 g. Spheronization was accomplished in 4 hours.Particles to be spheronized were made of PLGA composed of 75 mol %lactic acid residues and 25 mol % glycolic acid residues (75:25lactide/glycolide).

Materials

-   -   75:25 PLGA pellets: pellets made by melt-extrusion/pelleting        process, approximately 1 mm in length. Polymer was Boehringer        Ingelheim Resomer RG 755S (75:25 lactide/glycolide; IV ˜0.7)    -   Programmable stirrer/hotplate    -   Spinner flask    -   PVA, Aldrich 87-89% hydrolysed 31 000-50 000 MW Lot # 00514CQ

Method

-   -   1. To a 125-mL spinner flask charged with 100 mL of 0.2% PVA        solution (pH 6-7) stirring at 20-25° C. at 130 rpm was added ˜1        g of 75:25 PLGA pellets.    -   2. Heating was initiated and the solution was heated to 80° C.        over 15-30 minutes. Stirring was maintained.    -   3. The temperature was maintained at 80° C. for 4 hours.        Stirring was maintained.    -   4. Heating was discontinued and the solution temperature was        allowed to decrease to 20-25° C. Stirring was maintained.    -   5. Microspheres were collected by filtration and washed        copiously with deionized water to remove PVA.    -   6. Microspheres were dried and stored at 4° C.

Example 2

In this representative example, the ratio of suspending fluid to mass ofparticles was 500 mL:152 g (3.3 mL:1 g). Spheronization was accomplishedin 4 hours. Particles to be spheronized were made of PLGA composed of 75mol % lactic acid residues and 25 mol % glycolic acid residues (75:25lactide/glycolide).

-   -   1. PLGA cylinders from RG 755S (Resomer™, Boehringer Ingelheim)        were transferred to a 500-mL spinner flask containing 500 mL        0.2% PVA at room temperature and stirred at 280 rpm.    -   2. The temperature was increased to 80° C. and maintained at        80° C. for four hours with constant stirring.    -   3. Heating was discontinued and the solution temperature was        allowed to decrease to 20-25° C. Stirring was maintained.    -   4. Microspheres were collected by filtration and washed        copiously with deionized water to remove PVA.

Example 3

In this representative example, the ratio of suspending fluid to mass ofparticles is 6 mL:0.6 g (10 mL:1 g). Spheronization was accomplished byend-over-end mixing. Particles to be spheronized were made of PLGAcomposed of 50 mol % lactic acid residues and 50 mol % glycolic acidresidues (50:50 lactide/glycolide).

-   -   1. 600 mg of particles from melt-extruded 50:50 PLGA (RG 504H;        Resomer™, Boehringer Ingelheim) were added to a 10-mL vial        containing 6 mL of 0.2% PVA at room temperature and the vial        sealed.    -   2. The vial was attached to an end-over-end mixer, the mixer        placed inside an oven maintained at 65° C. and the mixer was        powered on.    -   3. End-over-end agitation was maintained for 4 hours, after        which the particles looked perfectly round by eye.

Example 4

In this representative example, the ratio of suspending fluid to mass ofparticles is 100 mL:0.5 g (200 mL:1 g). Change in shape from amorphousto ovoid was accomplished in 18.5 hours. Particles undergoing shapechange were made of PLGA composed of 75 mol % lactic acid residues and25 mol % glycolic acid residues (75:25 lactide/glycolide).

-   -   1. To a 250-mL beaker containing 100 mL 0.2% PVA solution at        room temperature and stirring at 270 rpm was added 501 mg of        PLGA pellets.    -   2. The temperature of the stirred suspension was raised from        21° C. to 70° C. and the conditions maintained for approximately        18.5 hours.    -   3. After 18.5 hours, the pellets had uniformly become ovoid,        like “Smarties™.”

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method of altering the shape of polymer particles, the methodcomprising: a) suspending the polymer particles in a suspending mediumat a temperature that effects melting of the polymer; and b) agitatingthe suspension for a time sufficient to effect a change, in shape of theparticles to result in shape altered polymer particles.
 2. The method ofclaim 1, wherein the polymer particle comprises a non-biologicalpolymer.
 3. The method of claim 1, wherein the polymer particle furthercomprises a pharmaceutically acceptable agent.
 4. The method of claim 3,wherein the pharmaceutically acceptable agent is selected from a smallmolecule, a carbohydrate, a lipid, a protein, or a nucleic acid.
 5. Themethod of claim 1, wherein the shape altered polymer particle is rigid.6. The method of claim 1, wherein the shape altered polymer particle iselastic.
 7. The method of claim 1, wherein the shape altered polymerparticle is biodegradable.
 8. The method of claim 1, wherein the polymerparticles are one or more of polyvinyl alcohol (PVA); polystyrene;polycarbonate; polylactide; polyglycolide; lactide-glycolide copolymers;polycaprolactone; lactide-caprolactone copolymers; polyhydroxybutyrate;polyalkylcyanoacrylates; polyanhydrides; polyorthoesters; albumin;collagen; gelatin; polysaccharides; dextrans; starches; methylmethacrylate; methacrylic acid; hydroxylalkyl acrylates; hydroxylalkylmethacrylates; methylene glycol dimethacrylate; acrylamide;bisacrylamide; cellulose-based polymers; ethylene glycol polymers andcopolymers; oxyethylene and oxypropylene polymers; polyvinyl acetate;polyvinylpyrrolidone; polyvinylpyridine; polyanhidrides; and latex. 9.The method of claim 8, wherein the polymer particles are selected frompolylactide, polyglycolide, and poly(lactic-co-glycolic acid) (PLGA).10. The method of claim 9, wherein the polymer particles are PLGA. 11.The method of claim 10, wherein the ratio of polylactide topolyglycolide in the PLGA is selected from about 90:10, about 75:25.about 65:35, and about 50:50.
 12. The method of claim 1, wherein thepolymer particles are produced by one or more of heatextrusion/pelleting, grinding, and cryo-grinding.
 13. The method ofclaim 1, wherein the suspending medium is an aqueous medium.
 14. Themethod of claim 13, wherein the aqueous medium is selected from water orsaline.
 15. The method of claim 13, wherein the aqueous medium furthercomprises one or more of Tris, Tyrodes, phosphate, citrate, or carbonatebuffers.
 16. The method of claim 13, wherein the aqueous medium furthercomprises an additional additive, wherein the additive prevents thepolymer particles from coalescing or aggregating.
 17. The method ofclaim 16, wherein the additional additive is selected from one or moreof a polyvinyl alcohol, a polypeptide, a detergent, or a hydrocarbon.18. The method of claim 1, wherein the method further comprises: c)cooling the suspension below the melting temperature of the polymer tomaintain the altered shape of the particles.
 19. The method of claim 1,wherein the method further comprises collecting the shape alteredparticles.
 20. The method of claim 1, wherein the altered shape of thepolymer particles is spherical, elliptical, elongated, bowling pin, egg,or oval.
 21. The method of claim 20, wherein the longest dimension ofthe altered particles is about 5 μm to about 5,000 μm.
 22. The method ofclaim 20, wherein the altered shape of the particles is spherical. 23.The method of claim 22, wherein the spherical polymer particles have adiameter from about 5 μm to about 5,000 μm.
 24. A method of preparingspherical polymer particles, the method comprising: a) suspendingnon-spherical polymer particles in a suspending medium at a temperaturethat effects melting of the polymer; and b) agitating the suspension fora time sufficient to effect a change in shape of the particles to resultin spherical polymer particles.
 25. The method of claim 24, wherein themethod further comprises: c) cooling the suspension below the meltingtemperature of the polymer to maintain the spherical shape of theparticles.
 26. The method, of claim 24, wherein the method furthercomprises collecting the spherical particles.
 27. A method of making adrug delivery particle, the method comprising: a) suspending an initialpolymer particle in a suspending medium at a temperature that effectsmelting of the polymer; b) agitating the suspension for a timesufficient to effect a change in shape of the initial particles toresult in shape altered particles; and c) incorporating apharmaceutically acceptable agent into the initial or the shape alteredparticles.
 28. The method of claim 27, wherein the incorporation of apharmaceutically acceptable agent is during production of the initialpolymer particles.
 29. The method of claim 27, wherein the incorporationof a pharmaceutically acceptable agent is during step b).
 30. The methodof claim 27, wherein the incorporation of a pharmaceutically acceptableagent occurs after obtaining shape altered particles.
 31. A sphericalparticle produced by the process of: a) suspending a polymer particle ina suspending medium at a temperature that effects melting of thepolymer; and b) agitating the suspension for a time sufficient to effecta change in shape of the particles to result in spherical particles 32.A spherical drug delivery particle produced by the process of: a)suspending an initial polymer particle in a suspending medium at atemperature that effects melting of the polymer; b) agitating thesuspension for a time sufficient to effect a change in shape of theinitial particles; and c) incorporating a pharmaceutically acceptableagent into the initial or spherical particles.